Glucokinase (abbreviated as GK in the present description; EC 2.7.1.1) is one of the four types of hexokinases (hexokinase IV) found in mammals. Hexokinases are enzymes that catalyze the conversion of glucose to glucose-6-phosphate in the first stage of the glycolysis system in cells, and the expression of GK is localized mainly in the liver and pancreatic beta cells. In pancreatic beta cells, GK functions as a detection mechanism of extracellular glucose concentration that regulates glucose-stimulated insulin secretion, while in the liver, the enzymatic reaction of GK serves as the rate-limiting step to regulate subsequent reactions such as glycolysis and glycogen synthesis. Although GK found in the liver and that found in pancreatic beta cells differ in the sequence consisting of 15 amino acids from the N-terminal due to a difference in splicing, their enzymatic properties are identical. In contrast to the enzymatic activities of the three types of hexokinases other than GK (types I, II and III) becoming saturated at a glucose concentration of 1 mM or less, GK exhibits low affinity for glucose, and the Km value thereof is near that of the physiological level of glucose in the blood at 8 to 15 mM. Thus, acceleration of GK-mediated intracellular glucose metabolism occurs in response to changes in blood glucose levels ranging from normal blood glucose levels (about 5 mM) to postprandial blood glucose levels (10 to 15 mM).
The hypothesis that GK functions as a glucose sensor in the liver and pancreatic beta cells has long been advocated (Non-Patent Documents 1 to 3). Recent research findings have demonstrated that GK actually plays an important role in maintaining systemic glucose homeostasis, thereby verifying this hypothesis. For example, mice in which glucokinase gene had been disrupted exhibited prominent hyperglycemia symptoms and died soon after birth, while GK hetero-deficient mice were observed to have defective glucose tolerance and impaired glucose-stimulated insulin secretion (Non-Patent Document 4). On the other hand, normal mice excessively expressing GK were observed to demonstrate decreased blood glucose levels and increased glycogen content in the liver, and these phenomena were similar to those in mice in which diabetes was artificially induced (Non-Patent Document 5).
In addition, GK also functions as a glucose sensor in humans, and has been demonstrated by recent research to play an important role in maintaining glucose homeostasis. Abnormalities have been discovered in the GK genes of family lineages exhibiting a form of juvenile-onset diabetes referred to as maturity onset diabetes of the young (MODY2), and a correlation was clearly observed between these cases and GK activity (Non-Patent Document 6). On the other hand, family lineages have also been found that possess a mutation that increases GK activity, and symptoms of fasting hypoglycemia accompanied by elevated plasma insulin concentrations have been observed in such family lineages (Non-Patent Document 7). On the basis of these reports, GK plays an important role in blood glucose regulation by functioning as a glucose sensor in mammals, including humans. Thus, substances having GK activating activity are considered to be useful as drugs for treatment of glycometabolic diseases including type II diabetes mellitus. Since GK activating substances can be expected to simultaneously demonstrate glucose uptake promoting activity and glucose release inhibitory activity in the liver as well as insulin secretion promoting activity in pancreatic beta cells in particular, they are predicted to be able to demonstrate potent therapeutic effects unable to be attained with existing drugs.
Pancreatic beta cell type GK has recently been determined to be expressed, being localized in the ventromedial hypothalamus (VMH) of the rat brain. The VMH has been conventionally known to be the site of neurons that respond to glucose concentration. In contrast to food intake decreasing when glucose is administered to rat ventricle, food intake is accelerated when glucose metabolism is inhibited by administration of the glucose analogue, glucosamine (Non-Patent Document 8). Electrophysiological experiments have demonstrated that glucose-responsive neurons are activated by responding to physiological changes in glucose concentrations (5 to 20 mM), and glucokinase has been determined to similarly function as a glucose sensor in peripheral tissue (Non-Patent Document 9). Thus, substances that give rise to glucokinase activation not only in the liver and pancreatic beta cells, but also in the VMH can be expected to demonstrate blood glucose lowering activity as well as activity that corrects obesity, which is considered to be a problem associated with numerous patients of type II diabetes mellitus.
On the basis of the aforementioned descriptions, substances having GK activating activity are useful as diabetes therapeutics and preventives, or as therapeutics and preventives of chronic complications of diabetes, including diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic heart disease and arteriosclerosis.
Furthermore, although a plurality of compounds having GK activating activity have been reported in the past, all of these have different structures from that of the compound of the present invention. For example, although Patent Document 1 describes a compound having an amide structure as an essential constituent thereof, the compound of the present invention has a pyrrole structure instead of an amide structure as an essential constituent thereof. In addition, although Patent Document 2 describes a compound having a condensed pyrrole, the compound of the present invention has a non-condensed pyrrole as an essential constituent thereof. Moreover, although Patent Document 3 describes a compound having a 3,5-di-substituted pyrazole or 1,2,4-triazole moiety, this differs from the 2,5-di-substituted pyrrole structure of the present invention. Although a plurality of compounds having GK activating activity have been reported in addition to those described in the above publications, all of these have different structures from that of the compound of the present invention (see, for example, Patent Documents 4 to 15 and Non-Patent Documents 10 and 11).
[Patent Document 1] International Publication No. WO2005/080359 Pamphlet
[Patent Document 2] International Publication No. WO2007/031739 Pamphlet
[Patent Document 3] International Publication No. WO2007/061923 Pamphlet
[Patent Document 4] International Publication No. WO2000/058293 Pamphlet
[Patent Document 5] International Publication No. WO2003/080585 Pamphlet
[Patent Document 6] International Publication No. WO2005/066145 Pamphlet
[Patent Document 7] International Publication No. WO2005/090332 Pamphlet
[Patent Document 8] International Publication No. WO2006/112549 Pamphlet
[Patent Document 9] International Publication No. WO2007/007886 Pamphlet
[Patent Document 10] International Publication No. WO2007/037534 Pamphlet
[Patent Document 11] International Publication No. WO2007/053765 Pamphlet
[Patent Document 12] International Publication No. WO2007/117381 Pamphlet
[Patent Document 13] International Publication No. WO2005/044801 Pamphlet
[Patent Document 14] International Publication No. WO2007/053662 Pamphlet
[Patent Document 15] International Publication No. WO2008/136428 Pamphlet
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